Southeast Asian populations have high rates of type 2 diabetes (T2D) despite low rates of obesity. This Southeast Asian Paradox has caused an extremely high public health and economic burden. While Southeast Asian-specific lower thresholds for defining obesity, set by the World Health Organization, underscore the particular susceptibility of these ethnic groups to T2D, the underlying biological and environmental causes for the excess diabetes in these populations are unknown. To date, genome-wide association studies of T2D have been completed in European populations, with none in other ethnic groups. These recent genetic findings only add to a Southeast Asian Paradox of T2D because several of the risk alleles found in Europeans have relatively low frequencies in the Asians. Our main aim is the identification of genetic susceptibility factors for T2D in Chinese living in Singapore, where there is a high prevalence of T2D. The study samples are derived from the ongoing Singapore Chinese Health Study, a population-based prospective cohort of 63,257 adult men and women assembled during 1993-1998 and continuously followed to date for incident morbidity and mortality. The NIH has been supporting the Singapore Chinese Health Study since its inception. There has been and continues to be significant cost- sharing by the National University of Singapore. All biological samples have already been collected and are ready for genotyping, and all environmental factors have been collected at baseline prior to the accrual of incident diabetes cases. Thus, we are in a unique position of conducting a genome-wide association study like none other to date in the following respects: 1) Very large size - 6,132 cases and 6,132 controls; 2) Nested case-control design - allowing for gene x environment interactions; 3) Unique, high risk population for which we currently have a weak understanding of T2DM etiology; 4) Extensive cost-sharing by the Genome Institute of Singapore and National University of Singapore, resulting in a high ratio of scientific discovery to monetary cost; and 5) Replication of our findings in two external Asian cohort studies. We believe the study proposed in this application will move the field forward in understanding the biological and environmental determinants of T2D in many Asian populations, and improve risk stratification so that those at greatest risk can be identified for early prevention or treatment. PUBLIC HEALTH RELEVANCE Southeast Asians have among the world's highest rates of type 2 diabetes despite low rates of obesity, a paradox for which the biological and environmental determinants remain unclear. The objective of this project is to identify the genetic and lifestyle risk factors for type 2 diabetes in a large population-based study of Singaporean Chinese adults. The study has tremendous potential to improve our understanding of type 2 diabetes risk in Southeast Asians, leading to improved prevention efforts.